This K23 application requests a period of career development to study advanced methods in Magnetic Resonance (MR) imaging and exploit them to study HIV-Dementia (HIV-D). Emerging MR methods provide microstructural information concerning white matter that cannot be obtained using other imaging techniques. Diffusion Tensor Imaging (DTI) is a non-invasive technique that may be useful in studying white matter integrity in normal, diseased or degenerating tissue in vivo. HIV-Dementia (HIV-D) is characterized by various pathologies involving white matter. This study represents an opportunity to evaluate information uniquely revealed by DTI in the context of other meaningful biological and clinical parameters. Subjects in this investigation will include well-characterized patients from a large, longitudinal cohort study_ef HIV-D. Extensive data is available from semi-annual evaluations over a number of years, including biological markers derived from plasma and CSF, as well as information concerning neurocognitive and psychiatric functioning. This study will determine whether microstructural measures of white matter integrity, derived using DTI, bear a relation to measures of advancing HIV infection (e.g. viral load and immune activation), severity of dementia and specific neuropsychiatric sequelae. In addition, the DTI findings will be evaluated in the context of biological markers of theoretical interest, including select measures of inflammation (e.g. TNF ) and endothelial integrity (e.g. MMP-9). These findings will contribute to an understanding of the pathogenesis of HIV-D and may provide insights concerning other CNS disorders. Experience gained during the proposed award will lay the foundation for further independent investigations of neurobiological factors in HIV-D.